A fundamental understanding of the pathogenesis of congenital kidney and urinary tract defects is crucial for developing new diagnostic and therapeutic strategies. To extend our research in this area, we propose to study embryonic patterning defects causing concurrent anomalies in the limbs and the urinary system, a phenomenon repeatedly observed in human patients. Luxate (Lx) and X-linked polydactyly (Xpl) are two classical mouse mutants with concurrent limb defects and a range of anomalies in the urinary system. We hypothesize that the Lx and Xpl mutations interrupt embryonic patterning events with pleiotropic effects on, or key regulatory circuits shared by, the development of the urinary system and the development of the limbs. We will first analyze the Lx and Xpl mice for a better understanding of the developmental processes that, when interrupted, cause the concurrent defects. In addition, we will combine the well-established positional cloning methods and the latest genome analysis tools to identify the mutations in the Lx and Xpl mutants. No known genes involved in congenital kidney and urinary tract abnormalities remain as candidates in the chromosomal intervals we have defined for Lx and Xpl. The identification of the mutations will thus reveal novel factors in the regulation of kidney development. The mechanistic studies and the mutation identification efforts are mutually supportive and are aimed at the common goal of illustrating the genetic basis and molecular mechanisms by which genetic mutations cause congenital renal diseases. PUBLIC HEALTH RELEVANCE: Urogenital defects are the second most common birth defects. Congenital kidney and urinary tract malformation is a major cause for renal failure in infants and children. The terminal pathological changes to the affected kidneys can be very similar in patients with very different causes. The hope for cure lies in the understanding of the causes and the correction of the initial cellular lesions. The Lx and Xpl mutant mice have concurrent limb and renal defects that resemble Acrorenal Syndrome in humans. In this application, we propose to identify the genetic mutations in the Lx and Xpl mutants and to reveal the molecular mechanisms by which these mutations cause the concurrent defects. Results from the proposed studies will contribute to the understanding of the genetic determinants and pathogenesis of birth defects in both the urinary system and the limbs. Such knowledge is crucial for developing new diagnostic and therapeutic strategies.